SEATTLE – Oct. 25, 2012 – Three investigators at Fred Hutchinson Cancer Research Center have won awards totaling nearly $3.6 million from the National Cancer Institute to participate in its “Provocative Questions Project” – an opportunity to address “potentially game-changing scientific questions” that could influence future directions of NCI-sponsored research.

In 2010, NCI director Harold Varmus led a series of workshops to define new directions for U.S. cancer research with the goal of ultimately funding more challenging and more creative research projects. The group came up with 24 questions to guide such research and put out a call for applications; this year’s awards go to projects that will attempt to answer 20 of those questions. Below are the three questions Fred Hutch researchers are addressing.

“Given the recent discovery of the link between a polyomavirus and Merkel cell cancer, what other cancers are caused by novel infectious agents and what are the mechanisms of tumor induction?”

In collaboration with others at the Hutchinson Center and at Washington University in St. Louis, Galloway will look for new links between infection and cancer. Nearly 20 percent of the world’s cancers are caused by infections, and these cancers are even more prevalent in immunosuppressed people, such as HIV-infected individuals and organ-transplant recipients, because dampened immune systems are less able to defend against the cancer-causing viruses. Well-known examples of infection-associated cancers include cervical cancer, which is caused by human papillomaviruses (HPV), and liver cancer, which is caused by hepatitis B virus (HBV). Galloway’s group was instrumental in drawing a definitive link between HPV, cervical and other anogenital cancers.

Her group will screen human DNA and RNA from tumor samples for the genetic signatures left by viruses and bacteria. The samples will come from HIV-positive patients at the Uganda Cancer Institute with lung cancer, non-HPV-associated genital cancers, or certain types of lymphomas. Uganda has one of the world’s highest rates of infection-associated cancers, in part because of the high levels of HIV infection in that country. The cancer types Galloway’s group are studying occur at much higher rates in HIV positive and other immunosuppressed people, so she suspects that some or all of these cancers may have infectious roots that are yet to be uncovered.

“If we find even one virus that’s associated with one type of cancer, it will make a huge difference,” Galloway said.

“Why do certain mutational events promote cancer phenotypes in some tissues and not in others?”

Despite certain similarities among all cancer cells, cancers in different tissues tend to behave very differently. For example, spontaneous mutations in certain genes can frequently lead to cancers in one tissue type but not another. The growing tumor’s local environment is clearly very important to its specific development, but researchers currently understand very little about these tissue-specific effects. This means that we lack targeted therapies for most cancer types.

Paddison and colleagues are studying gliobastoma multiforme, the most aggressive and common form of brain cancer in adults. They have developed a technique to isolate the tumor-forming stem cells from patients’ tumors and grow them in the lab, meaning they have patient-specific experimental models of tumor cells. Unlike traditional cancer cells used for lab experiments, the cells Paddison studies retain their patient- and tissue-specific genetic and epigenetic characteristics.

In collaboration with Seattle biotechnology company Sage Bionetworks, Paddison’s group is using a gene knockdown technology called RNA interference to disable genes one at a time in these brain tumor cells to determine which genes are necessary for the tumor’s survival. This project will help the researchers understand which cellular processes are important for brain tumor development and survival, and it ultimately could lead to targeted therapies for glioblastomas.

“Are there new technologies to inhibit traditionally “undruggable” target molecules, such as transcription factors, that are required for the oncogenic phenotype?”

Transcription factors, proteins that activate or de-activate genes, play important roles in cancer development but have traditionally proved to be difficult drug targets. Eisenman studies the transcription factor known as Myc, which is involved in activating many different genes in many different cell types. His group has characterized how Myc goes haywire in cancerous cells, and has found many other proteins that interact with Myc to regulate its function. In healthy cells, Myc’s gene-activating activity is balanced by another protein, Mxd, which represses many of the genes that Myc turns on.

“When Myc is deregulated in cancers, this balance is lost,” Eisenman said, and many genes that would normally remain silent are aberrantly activated.

Inhibiting Myc’s abundant activity in cancer cells could vastly improve cancer treatments, but finding drugs to bind and disrupt Myc has been difficult due to its large binding surfaces. Eisenman’s group plans to use a type of experimental evolution to find a protein piece that can disrupt Myc but not Mxd. They’ll do this by rapidly changing the peptide’s sequence in the lab and selecting for those that best bind to Myc. The researchers will then test whether these potential anti-Myc drugs can kill off cancer cells in the lab.

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At Fred Hutchinson Cancer Research Center interdisciplinary teams of world-renowned scientists – including three Nobel laureates – seek new and innovative ways to prevent, diagnose and treat cancer, HIV/AIDS and other life-threatening diseases. The Hutchinson Center’s pioneering work in bone marrow transplantation led to the development of immunotherapy, which harnesses the power of the immune system to treat cancer with minimal side effects. An independent, nonprofit research institute based in Seattle, the Hutchinson Center houses the nation’s first and largest cancer prevention research program, as well as the clinical coordinating center of the Women’s Health Initiative and the international headquarters of the HIV Vaccine Trials Network. Private contributions are essential for enabling Hutchinson Center scientists to explore novel research opportunities that lead to important medical breakthroughs. For more information visit www.fhcrc.org or follow the Hutchinson Center on Facebook, Twitter or YouTube.

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